Molecular Enhancement of Alpha 7 Integrin to Ameliorate Muscular Dystrophy

Duchenne muscular dystrophy is the most common form of muscular dystrophy and it is lethal; most patients dye before their early twenties. This disease is caused by mutations in the gene encoding dystrophin, a member of the dystrophin protein complex that links the extracellular matrix to the cytoskeleton in skeletal muscle. The alpha7beta1 integrin also links laminin in the extracellular matrix to actin in skeletal muscle. It has been shown that transgenic overexpression of the alpha7 integrin chain in mdx/utr (-/-) mice, a model for Duchenne muscular dystrophy, ameliorates dystrophic pathology and prolongs survival. To translate this result into a therapy for patients, myogenic cells from the alpha7(+/-) mice that have the beta galactosidase reporter driven by the alpha7 integrin promoter were screened for molecules that enhance alpha7 expression. Two such molecules were identified: HTCB and valproic acid increase alpha7 levels about 1.4-fold and 2-fold respectively. Valproic acid also activates the Akt/mTOR pathway, promoting myotube hypertrophy and survival. To test their effects in vivo, the molecules were administered to mdx/utr (-/-) mice. Valproic acid injected mice have decreased fibrosis and contractures, improved mobility and kyphosis, decreased inflammatory cell content and cardiomyopathy and increased myofiber integrity. HTCB injected mice have increased myofiber integrity and show elevated alpha7 integrin expression in muscle. Together, these results represent important milestones towards developing an alpha7beta1 integrin based complementary gene therapy for Duchenne muscular dystrophy.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Microbiology

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2015

Author dc:creator

• Gurpur, Praveen B.

Contributors dc:contributor

• Kaufman, Stephen J.

• Biology, Cell

Language dc:language

eng

Identifier

(MiAaPQ)AAI3290242

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/86697